tbuckley/cabot-search huggingface dataset:
NCMP-07. HEADACHE PRESENTATION AND MANAGEMENT IN VON HIPPEL-LINDAU (VHL)-ASSOCIATED HEMANGIOBLASTOMAS
Authors: Sanah Vohra, Yelena Malkhasyan, Anubhav Chandla, Michael Gordon, Brian Shuch, Jerome Graber, Isaac Yang
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Hemangioblastomas are the most common brain tumors among patients with Von Hippel-Lindau (VHL) disease. Common characteristics of these benign tumors, such as tumor growth, peritumoral edema, and cystic expansion, may lead to neurologic morbidity and/or mortality. Thus, early diagnosis based on symptom presentation and appropriate treatment is paramount to VHL-associated hemangioblastoma management. METHODS We conducted a systematic review of PubMed, Scopus, Cochrane, Embase, and Web of Science databases using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We identified studies reporting pre-diagnostic symptoms and post-diagnostic treatments among patients with VHL-associated hemangioblastomas. RESULTS Data from 150 patients were analyzed. The average age at presentation was 35.3 years (range: 18-75) and 52.7% of patients were female. Headache was the most common presenting symptom (73.3%). Other presenting symptoms included balance or gait disturbances (42%), ataxia (41.3%), nausea (24.3%), emesis (24.3%), dysmetria (15.5%), swallowing difficulties (11.3%), and singultus (10.7%). Anatomically, 98.7% of tumors were in the posterior fossa, specifically 69% in the cerebellum and 30% in the brainstem. Approximately 62.8% of patients had tumor associated cysts. A majority of the patients (98.7%) underwent gross-total resection of the tumor and cyst drainage as needed. Other common treatments included radiotherapy, gamma-knife surgery, and ventriculoperitoneal shunt placement. CONCLUSION Patients with VHL-associated hemangioblastomas commonly presented with headaches, balance or gait difficulties, and ataxia. Tumors were generally found in the posterior fossa and were associated with cysts. Gross-total resection was the main treatment offered to patients with these tumors.
NIMG-81. ASSOCIATION OF THE ORIGIN OF CRANIOPHARYNGIOMA WITH OPTIC TRACT EDEMA
Authors: Takuma Kodama, Osamu Akiyama, Yuzaburo Shimizu, Mario Suzuki, Shinichiro Teramoto, Akihide Kondo
Journal: Neuro-Oncology (2023)

Abstract OBJECTIVE Optic tract edema (OTE) is a useful finding in the diagnosis of craniopharyngioma (CP). However, the pathogenesis of OTE is not fully understood. In this study, we investigated the presence of OTE depending on the site of origin of CP. METHODS We reviewed 48 patients with CP who underwent surgical treatment at Juntendo University Hospital between March 2010 and February 2023 and investigated their size, location, presence of OTE, pathological subtypes, and genetic abnormalities. Tumors were classified into four groups based on their origin: retrochiasmatic (RC) type, prechiasmatic (PC) type, intrasellar (IS) type, and intra-third-ventricle (ITV) type. RESULTS Forty-eight cases were included in this study. The number of cases of RC, PC, IS, and ITV types were 29, 8, 3, and 8, respectively. OTE was shown in 21 cases. Among them, RC type was the most common location (18 cases, 86%) with significant differences. The cystic component of the tumor was in contact with the optic tract in 15 cases, which was more common than the solid component. DISCUSSION Possible causes of OTE include cytotoxic edema associated with inflammation, angiogenic edema due to leakage of serum components from the tumor, leakage of fluid components from the cyst, and enlargement of the Virchow-Robin space in the optic disc. In this study, many of the cases with OTE have cystic components in contact with the optic tract, suggesting leakage of fluid components from the cyst as the pathogenesis of OTE. The presence of OTE can be a new factor to determine the surgical approach since CP with OTE is thought to extend posteriorly to the optic chiasm. CONCLUSIONS OTE is often associated with RC type CP and is thought to be caused by leakage of fluid from the cyst.
TMIC-35. TUMOR CELL-DERIVED SPERMIDINE ACCELERATES GLIOBLASTOMA PROGRESSION VIA LYMPHOCYTE DEPLETION
Authors: Kristen Kay, Defne Bayik, Zeneng Wang, Jason Miska, J Mark Brown, Stanley L Hazen, Justin Lathia
Journal: Neuro-Oncology (2023)

Abstract Therapeutic resistance in glioblastoma (GBM) is partly due to a highly immunosuppressive environment resulting in ineffective anti-tumor immune response. This likely underlies the lack of success of immunotherapies that are successful in other cancers; novel ways to target this environment are needed. Naturally occurring polyamines (PAs) have been identified as a putative therapeutic target in other cancers based on their increased presence and correlation to poorer prognosis. Under normal conditions, spermidine (SPD) – a member of the PA family – is critical for cell growth. While PAs are increased in GBM patients, little is known about their impact on GBM growth. In syngeneic immunocompetent mouse glioma models, mass spectrometry revealed that SPD increases in the tumor microenvironment and circulation as compared to non-tumor-bearing mice. We treated the same models with exogenous SPD, which significantly decreased survival. However, in immunocompromised mice, no survival difference was observed, suggesting SPD drives GBM progression through immune interaction. Immune profiling the mouse models treated with SPD showed peripheral reduction of CD4+ and CD8+ T cells. Due to the observed T cell changes, we repeated the exogenous SPD paradigm in RAG1 knockout mice that do not have circulating B/ T cells. Similar to NSG mice, we see no survival difference, indicating that SPD drives GBM by affecting lymphoid cells. To investigate the origin of SPD in our models, we knocked down the rate limiting enzyme of the PA biosynthesis pathway in glioma cells in immunocompetent mice. Mice implanted with knockdown cells showed a robust survival extension, suggesting that tumor cells produce SPD which affects the tumor microenvironment. Ongoing studies are evaluating uptake from the environment on the progression of GBM using pharmacological inhibitors. Understanding the interactions of PAs and the immune response as a whole will allow us to alter the environment to enhance immunotherapeutic efficacy.
EXTH-40. PHOTODYNAMIC ONCOLYTIC VIRUS THERAPY FOR CENTRAL NERVOUS SYSTEM MALIGNANCIES
Authors: Kazuhide Shimizu, Andranik Kahramanian, Taketoshi Maehara, Hiroaki Wakimoto
Journal: Neuro-Oncology (2023)

Abstract Oncolytic viruses (OVs) have emerged as a clinical therapeutic modality potentially effective to treat cancers that evade conventional therapies, including central nervous system malignancies. Rationally designed combinatorial strategies can augment the efficacy of OVs by boosting tumor-selective cytotoxicity and modulating the tumor microenvironment (TME). Photodynamic therapy (PDT) of cancer not only mediates direct neoplastic cell death but also primes the TME to sensitize the tumor to secondary therapies. This allows for the combination of two potentially synergistic therapies with broader targets. Here, we created G47Δ-KR, clinical oncolytic herpes simplex virus G47Δ that expresses photosensitizer protein KillerRed (KR). Optical properties and cytotoxic effects of G47Δ-KR infection followed by amber LED illumination were examined in human glioblastoma (GBM) and malignant meningioma (MM) models in vitro. G47Δ-KR infection of tumor cells mediated KR expression that was activated by amber LED and produced reactive oxygen species, leading to cell death that was more robust than G47Δ-KR without light. In vivo, we tested G47Δ-KR-based PD-OV therapy employing intratumoral injection of G47Δ-KR followed by amber laser (wavelength: 585 nm) tumor irradiation in GBM and MM xenografts. PD-OV therapy was feasible in GBM and MM xenografts and resulted in potent anti-tumor effects that were superior to G47Δ-KR alone (without laser) or laser alone. RNA sequencing analysis of post-treatment tumor samples revealed PD-OV therapy-induced increases in TME infiltration of variable immune cell types. This study thus demonstrated the proof-of-concept that G47Δ-KR enables PD-OV therapy for neuro-oncological malignancies and warrants further research to advance potential clinical translation.
TMIC-67. GLIOBLASTOMA AUGMENTS SYSTEMIC IMMUNUNOSUPPRESSION UPON LOSS OF TESTOSTERONE VIA ALTERATION OF GLUCOCORTICOIDS PRODUCTION
Authors: Juyeun Lee, Justin Lathia, Yoon-Mi Chung, Nima Sharifi, Yue Hao, Michael Berens
Journal: Neuro-Oncology (2023)

Abstract While sex differences in incidence, genetics, and immune changes are established in glioblastoma (GBM), the specific contribution of sex hormones to these differences has not been fully explored. Testosterone has been shown to have a pro-tumorigenic effect on human and mouse GBM tumor cells. However, the systemic effect of testosterone in an immune competent model has not been tested. To test this, we performed castration or sham surgery on C57BL/6 male mice, followed by intracranial implantation of syngeneic glioma cells. Surprisingly, castrated mice exhibited more aggressive tumor growth compared to sham surgery controls, and this castration-induced aggressiveness could be reversed by administering exogenous testosterone. This finding was further confirmed by chemically blocking androgen receptor signaling using enzalutamide. We observed a significant increase in adrenocorticotropic hormone (ACTH) levels in the serum from castrated mice compared to the sham group after tumor implantation. Additionally, mass spectrometry analysis detected elevated levels of circulating glucocorticoids in castrated mice, and pharmacological blockade of glucocorticoid receptor using mifepristone reversed the shorted survival in castrated mice, but not in sham control. Flow analysis revealed decreased production of anti-tumor cytokines such as IFN-γ and TNF-α in CD4+ and CD8+ T cells from tumors and lymph nodes in castrated mice, suggesting systemic immunosuppression in these animals. Indeed, castration of immune-compromised mice, specifically NSG and RAG1KO strains, did not result in reduced survival. Moreover, when GBM cells were subcutaneously implanted into the flank, tumor growth in castrated mice was decelerated compared to sham controls. We also observed significantly lower ACTH levels in the flank tumor model compared to the brain tumor model, indicating a brain-specific effect of steroid hormones on tumor control. Taken together, these findings demonstrate that testosterone regulates T cell function through glucocorticoids, ultimately affecting GBM growth in a site-specific manner.
NCOG-37. BELZUTIFAN IN ADULTS WITH VHL-ASSOCIATED CENTRAL NERVOUS SYSTEM HEMANGIOBLASTOMA: A SINGLE-CENTER EXPERIENCE
Authors: Bryan Neth, Mason Webb, Jessica White, Joon Uhm, Pavel Pichurin, Ugur Sener
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Belzutifan is a selective inhibitor of hypoxia-inducible factor 2-alpha that has been FDA approved for Von Hippel–Lindau (VHL) syndrome-associated tumors. There is limited real-world evidence in CNS hemangioblastoma. Our objective was to report on our clinical experience with belzutifan. METHODS We retrospectively reviewed our institutional (Mayo Clinic Rochester) experience of belzutifan in adults (18 years or older) with VHL and craniospinal hemangioblastomas not amenable to surgery. The study period was October 2021 to March 2023. RESULTS 4 patients (all female) with a median age of 36 years at time of belzutifan initiation were included. Median duration of therapy at last follow-up was 11 months (6-17 months). All patients had radiographic response to therapy after a median of 3 months (2-5 months), with maximal response to therapy after a median of 8 months (3-17 months). Therapy was well tolerated. The most common adverse effect was anemia. No patients had treatment pauses or dose adjustments due to toxicity. No patients experienced hypoxia. DISCUSSION We showed that belzutifan is safe and well-tolerated with strong disease response for CNS hemangioblastoma in adults with VHL, supporting continued use of belzutifan in this patient population. Future studies should assess duration of treatment, effects of cessation after long-term use, and markers of therapeutic response.
NIMG-30. DEEP LEARNING SEGMENTATION OF INFILTRATIVE AND ENHANCING CELLULAR TUMOR IN POST-TREATMENT GLIOBLASTOMA PATIENTS WITH MULTI-SHELL DIFFUSION MRI
Authors: Louis Gagnon, Diviya Gupta, George Mastorakos, Nathan White, Vanessa Goodwill, Carrie McDonald, Thomas Beaumont, Christopher Conlin, Tyler Seibert, Jona Hattangandi-Gluth, Santosh Kesari, Jessica Schulte, David Piccioni, Anders Dale, Niky Farid, Jeffrey Rudie
Journal: Neuro-Oncology (2023)

Abstract Multimodal MRI is used for the evaluation of tumor burden in glioblastoma (GBM) patients after surgical resection, radiation, and chemotherapy. However, it can be challenging to identify non-enhancing infiltrative tumor and differentiate recurrent enhancing tumor from post-treatment changes. Restriction spectrum imaging (RSI), an advanced multishell diffusion technique, has shown promise in distinguishing cellular tumor from edema and enhancing post-treatment changes including pseudoprogression and radiation necrosis. We developed a convolutional network (nnUNet) that incorporates traditional multimodal MRI with DSC perfusion and RSI to detect and quantify enhancing and nonenhancing cellular tumor in post-treatment glioblastoma patients. This cellular tumor segmentation network was evaluated in a cohort of 186 post-treatment GBM patients (55.5 +/- 13.7 years, 158 male) with 243 timepoints using 5-fold cross validation. Cellular tumor volumes were then used to predict overall survival (OS) and progression free survival (PFS) in 94 patients with imaging within 3 months of initial surgery. Accuracy for segmenting cellular tumor as measured by the Dice-similarity coefficient was 0.77 (IQR 0.55-0.87) and the AUC of the ROC curve for detecting residual/recurrent tumor compared to post-treatment changes was 0.86. The predicted cellular tumor volumes were an independent hazard over age, sex, GTR status and conventional enhancing residual tumor for both OS (p=0.0003) and PFS (p=0.0004). The tumor segmentation network was validated in an external dataset of 22 GBM patients (55 timepoints) with a median Dice of 0.73 and AUC of 0.91. Survival prediction was validated in a different external dataset of 70 post-treatment GBM patients, with cellular tumor volumes being an independent predictor of OS (p=0.03). In conclusion, deep learning models incorporating advanced imaging can accurately segment enhancing and nonenhancing cellular tumor, which can help distinguish recurrent/residual tumor from post-treatment changes and predict OS and PFS.
PATH-59. SYSTEMATIC CHARACTERIZATION OF ANTIBODY-DRUG CONJUGATE TARGETS IN CENTRAL NERVOUS SYSTEM TUMORS
Authors: Shannon Coy, Jong Suk Lee, Sabrina J Chan, Terri Woo, Jacquelyn Jones, Sanda Alexandrescu, Patrick Wen, Peter K Sorger, Keith Ligon, Sandro Santagata
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Antibody-drug conjugates (ADCs) enhance the specificity of cytotoxic drugs by directing them to cells expressing target antigens. Multiple ADCs are FDA-approved for solid cancers, including those expressing ERBB2/HER2, TACSTD2/TROP2, NECTIN4, folate receptor 1 (FOLR1), and tissue factor (CD142/TF). Recently, a next-generation ADC targeting HER2 (Trastuzumab-Deruxtecan) increased survival and reduced growth of brain metastases in treatment-refractory metastatic breast cancer, even in tumors with low HER2 expression. Thus, low-level ADC target expression may be sufficient for treatment responsiveness, and CNS tumors may be responsive to next-generation ADC. However, ADC target expression is poorly characterized in most CNS tumors. METHODS To systematically characterize ADC target expression in CNS tumors, we analyzed publicly available RNA-sequencing and proteomic data from the Children’s Brain Tumor Network (n=188 tumors) and GEO RNA-expression datasets (n=356 tumors) to evaluate expression of 14 potential ADC targets that are FDA-approved or under clinical investigation in solid cancers. We also used immunohistochemistry to score the levels of HER2, HER3, NECTIN4, TROP2, CLDN6, CLDN18.2, and CD276/B7-H3 protein in glioblastoma (GBM), oligodendroglioma, meningioma, ependymoma, pilocytic astrocytoma, medulloblastoma, atypical teratoid/rhabdoid tumor (AT/RT), adamantinomatous craniopharyngioma (ACP), papillary craniopharyngioma (PCP), and primary CNS lymphoma (n=575 total tumors). RESULTS Multi-modal pan-CNS analysis showed consistent subtype-specific expression of ADC target proteins. Most tumors expressed HER3, B7-H3, and NECTIN4. Ependymomas (n=44) strongly expressed HER2 (36/44; 81% of cases by IHC), while meningiomas weakly-moderately expressed HER2 in most tumors (201/234; 86%). ACP (n=15) and PCP (n=3) strongly expressed B7-H3 (100% of cases), with TROP2 and HER2 expression in whorled ACP epithelium (100% of cases). AT/RT strongly expressed CLDN6 (8/9; 89%). GBM showed little subtype-specific marker expression, suggesting a need for further target development. CONCLUSIONS CNS tumors exhibit subtype-specific expression of ADC targets including several FDA-approved for other indications. Clinical trials of ADCs in CNS tumors may therefore be fruitful.
NIMG-34. TEMPORAL MUSCLE THICKNESS AS A PROGNOSTIC MARKER IN A REAL-LIFE COHORT OF NEWLY DIAGNOSED <i>MGMT</i> PROMOTER METHYLATED GLIOBLASTOMA PATIENTS: A MULTICENTRIC IMAGING ANALYSIS
Authors: Lazaros Lazaridis, Christoph Moenninghoff, Elisabeth Bumes, Dorothee Cäcilia Spille, Michael Müther, Tim Schulz, Sina Heider, Sarina Agkatsev, Teresa Schmidt, Tobias Blau, Christoph Oster, Walter Stummer, Almuth Friederike Kessler, Clemens Seidel, Oliver Grauer, Peter Hau, Ulrich Sure, Kathy Keyvani, Ulrich Herrlinger, Christoph Kleinschnitz, Martin Stuschke, Ken Herrmann, Cornelius Deuschl, Björn Scheffler, Sied Kebir, Martin Glas
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND In cranial MRI assessed temporal muscle thickness (TMT) correlates with lumbar skeletal muscle mass, which serves as surrogate marker of sarcopenia. Prior research has identified TMT as a prognostic marker in glioblastoma. However, incorporation into clinical practice is challenging due to the heterogeneity of previous studies and the absence of established cutoff values. To address this, we conducted a multicenter analysis to validate recently proposed sex-specific cutoff values in a homogeneous real-life cohort of newly diagnosed MGMT promoter-methylated glioblastoma patients uniformly treated with combined CCNU/temozolomide. We implemented a balanced control cohort for comparison. METHODS TMT was measured at baseline using preoperative or early postoperative MRI and in the disease course using the first MRI after completion of radiotherapy. Patients were TMT-based divided into “at risk of sarcopenia” or “normal muscle status”. Kaplan-Meier statistics and multivariable Cox regression analysis were used for correlation with survival. RESULTS In total, n = 126 patients were analyzed (n = 66 received CCNU/temozolomide; n = 60 received temozolomide). Patients with normal muscle mass at baseline (&amp;gt; 6,3 mm for men; &amp;gt; 5,2 mm for women) had significantly prolonged mOS (44.3 versus 16.7 months for CCNU/temozolomide; 29.5 versus 17.4 months for temozolomide) compared to those at risk of sarcopenia. In a multivariable Cox regression analysis, normal muscle mass (HR: 0.39, 95% CI: 0.23-0.66; p = 0.0003) and age at diagnosis of &amp;lt; 50 years (HR: 0.42, 95% CI: 0.22-0.79; p = 0.0067) were significant prognostic markers. Longitudinally, survival was best in patients with lack of TMT decline. CONCLUSIONS This analysis suggests TMT to serve as a prognostic marker in glioblastoma patients treated with CCNU/temozolomide or with temozolomide. However, for TMT assessment to be implemented in a generalizable manner, such as for patient selection for therapeutic measures, further validation in prospective controlled trials is necessary.
PATH-56. SUPRATENTORIAL NEUROEPITHELIAL TUMORS WITH NOVEL <i>PLAGL1</i> FUSIONS: 2 CASE REPORTS
Authors: Cassandra Helfer, Malcolm McDonald, Akash Patel, Sameer Sheth, Ganesh Rao, Ali Jalali, Kalman Katlowitz, Alfredo Echeverria, Oluwaseun Ogunbona, Kenneth Aldape, Zied Abdullaev, Hsiang-Chih Lu, Ashley Holloman, Jacob Mandel
Journal: Neuro-Oncology (2023)

Abstract Neuroepithelial tumors with pleomorphic adenoma gene-like (PLAGL1) fusions represent a distinct subgroup of neoplasms that have been recently identified. These fusions are quite rare and most commonly associated with fusions in the EWSR1 or FOXO1 genes. Limited reports in literature have indicated a median age of diagnosis of 6.2 years and poor progression-free survival at 35 months. Here we present two cases of patients with neuroepithelial tumors with PLAGL1 fusions. Case 1 was a 49 year old male who underwent resection of a left frontal lobe mass at 2 year old that was reported as a low grade ependymoma. He did not receive radiation or chemotherapy and subsequently developed seizures in childhood. At age 47, he presented with worsening seizures and MRI brain revealed a 4.5 cm mass in the left frontal lobe with serpiginous enhancement. He underwent surgical resection and molecular profiling demonstrated PLAGL1-FOXO1 fusion. Case 2 was an 18 year old female presenting with generalized tonic-clonic seizures. MRI brain demonstrated a 1.4 x 1.2 cm cortical and subcortical lesion in the right parietal lobe. Following surgical resection, pathology reported a low grade neuroepithelial neoplasm with ependymal-like features. Molecular profiling showed PLAGL1-EWSR1 fusion. As PLAGL1 fusions are not yet characterized in the WHO classification system, these cases aid in tumor characterization and highlight the importance of molecular and methylation analysis for accurate tumor classification. Case 2 presents a notable variation from reported age of presentation of 6.2 years with diagnosis at 18 years of age, indicating these tumors may also present in young adulthood. Additionally, Case 1 demonstrated 45 years progression-free survival compared to previously reported median of 35 months, suggesting outcomes may be heterogeneous with potential for prolonged survival. Further research is needed to better elucidate the imaging, clinical course, and prognosis for tumors with this novel fusion.